The filoviruses, Ebola and Marburg viruses (EBOV and MARV), are emerging, negative-strand RNA viruses associated with outbreaks of severe viral hemorrhagic fever. The virulence and emerging nature of these zoonotic pathogens makes them a significant threat to human health, potential agents of bioterrorism, and NIAID category A priority pathogens. Currently, no approved anti-filovirus therapeutics are available. Among the proteins encoded by EBOV, VP35 is of particular interest for antiviral development because it makes a critical contribution to pathogenesis through its role in viral replication and host immune suppression. The Basler lab first identified the VP35 protein as an EBOV-encoded inhibitor of the RIG-I signaling pathway, which normally functions to trigger IFN?/? production in response to RNAs produced during viral infection. VP35 also functions as a co-factor in the filoviral replication complex. Important insight into the molecular basis by which VP35 IFN inhibitory domain (IID) participates in the viral RNA polymerase complex and inhibits the RIG-I pathway have recently been provided by structural studies from the Amarasinghe laboratory. Our recent collaborative studies have identified a novel interaction between Ebola VP35 and NP proteins that will be exploited for high-throughput screen (HTS) development. Since we are targeting a protein-protein interface, we will use fragment screens to validate the interface. Studies here are aimed to provide highly sensitive assays that can be converted to HTS assays in order to identify replication inhibitors.

Public Health Relevance

Pathogenic Ebola and Marburg viruses cause rare but deadly outbreaks among human populations. Recent outbreak in West-Africa coupled with a rising potential of misuse in the form of bioterrorism, underscore the importance of the proposed studies to global health. The current studies are important as they will develop high-throughput screens to identify replication inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI123926-02
Application #
9208738
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Davis, Mindy I
Project Start
2016-02-01
Project End
2019-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
2
Fiscal Year
2017
Total Cost
$638,961
Indirect Cost
$106,798
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Liu, Gai; Nash, Peter J; Johnson, Britney et al. (2017) A Sensitive in Vitro High-Throughput Screen To Identify Pan-filoviral Replication Inhibitors Targeting the VP35-NP Interface. ACS Infect Dis 3:190-198
Chatterjee, Srirupa; Luthra, Priya; Esaulova, Ekaterina et al. (2017) Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses. Nat Microbiol 2:17101
Xu, Wei; Luthra, Priya; Wu, Chao et al. (2017) Ebola virus VP30 and nucleoprotein interactions modulate viral RNA synthesis. Nat Commun 8:15576
Chatterjee, Srirupa; Basler, Christopher F; Amarasinghe, Gaya K et al. (2016) Molecular Mechanisms of Innate Immune Inhibition by Non-Segmented Negative-Sense RNA Viruses. J Mol Biol 428:3467-82
Johnson, Britney; Li, Jing; Adhikari, Jagat et al. (2016) Dimerization Controls Marburg Virus VP24-dependent Modulation of Host Antioxidative Stress Responses. J Mol Biol 428:3483-94
Leung, Daisy W; Amarasinghe, Gaya K (2016) When your cap matters: structural insights into self vs non-self recognition of 5' RNA by immunomodulatory host proteins. Curr Opin Struct Biol 36:133-41